Escalating dosing regimen for effecting weight loss and treating obesity

ABSTRACT

The present invention is drawn to novel topiramate compositions as well as methods for effecting weight loss, e.g., in the treatment of obesity and related conditions, including conditions associated with and/or caused by obesity per se. The present invention features an escalating dosing regimen adapted for the administration of topiramate and optionally a sympathomimetic agent such as phentermine or bupropion, in the treatment of obesity and related conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 16/220,276, filedDec. 14, 2018, which is a continuation of U.S. Ser. No. 15/150,907,filed May 10, 2016, which is a continuation of U.S. Ser. No. 14/878,235,filed Oct. 8, 2015 which is a continuation of U.S. Ser. No. 14/679,754,filed Apr. 6, 2015 which is a continuation of U.S. Ser. No. 14/495,250,filed Sep. 24, 2014, now U.S. Pat. No. 9,011,906, which is acontinuation of U.S. Ser. No. 14/048,416, filed Oct. 8, 2013, now U.S.Pat. No. 8,895,057, which is a continuation of U.S. Ser. No. 12/481,548,filed Jun. 9, 2009, now U.S. Pat. No. 8,580,299, which is acontinuation-in-part of U.S. Ser. No. 12/135,953, filed Jun. 9, 2008.The contents of each of these applications are incorporated by referencein their entirety.

BACKGROUND OF THE INVENTION

The prevalence of obesity in both children and adults is on the rise infirst world countries, especially in the United States, as well as inmany developing countries such as China and India. Many aspects of aperson's life are affected by obesity, from physical problems such asknee and ankle joint deterioration, to emotional problems resulting fromself-esteem issues and society's attitude towards heavy people. Themedical problems caused by obesity can be serious and oftenlife-threatening and include diabetes, shortness of breath and otherrespiratory problems such as asthma and pulmonary hypertension,gallbladder disease, dyslipidemia (for example, high cholesterol or highlevels of triglycerides) and dyslipidemic hypertension, osteoarthritisand other orthopedic problems, reflux esophagitis (heartburn), snoring,sleep apnea, menstrual irregularities, infertility, problems associatedwith pregnancy, gout, cardiovascular problems such as coronary arterydisease and other heart trouble, muscular dystrophy, and metabolicdisorders such as hypoalphalipoproteinemia, familial combinedhyperlipidemia, and Syndrome X, including insulin-resistant Syndrome X.In addition, obesity has been associated with an increased incidence ofcertain cancers, notably cancers of the colon, rectum, prostate, breast,uterus, and cervix.

Obesity substantially increases the risk of morbidity from hypertension,dyslipidemia, type II diabetes, coronary heart disease, stroke,gallbladder disease, osteoarthritis and endometrial, breast, prostate,and colon cancers. Higher body weights are also associated withincreases in all-cause mortality. Many of these problems are relieved orimproved when the afflicted individual undergoes permanent significantweight loss. Weight loss in these individuals can also promote asignificant increase in longevity.

Strategies for treating obesity and related disorders have includeddietary restriction, increased physical activity, pharmacologicalapproaches, and even surgery, with the choice depending, at least inpart, on the degree of weight loss one is attempting to achieve as wellas on the severity of obesity exhibited by the subject. For example,treatments such as a low-calorie, low-fat diet and/or regular exerciseare often adequate with individuals who are only mildly overweight. Thedifficulty in maintaining long-term weight loss through diet andbehavior modification, however, has led to an increasing interest inother avenues for treatment, particularly pharmacotherapy.

Traditional pharmacological interventions typically induce a weight lossof between five and fifteen kilograms; if the medication isdiscontinued, renewed weight gain often ensues. Surgical treatments arecomparatively successful and are reserved for patients with extremeobesity and/or with serious medical complications.

The above treatments can be enhanced by controlled use ofover-the-counter appetite suppressants including caffeine, ephedrine andphenylpropanolamine (Acutrim®, Dexatrim®). Moreover, prescriptionmedications including amphetamine, diethylpropion (Tenuate®), mazindol(Mazanor®, Sanorex®), phentermine (Fastin®, Ionamin®), phenmetrazine(Preludin®), phendimetrazine (Bontrol®, Plegine®, Adipost®, Dital®,Dyrexan®, Melfiat®, Prelu-2®, Rexigen Forte®), benzphetamine (Didrex®)and fluoxetine (Prozac®) are often used in the treatment of seriouslyoverweight and/or obese subjects or patients.

While society has seen tremendous advances in the field ofpharmaceuticals, there are, of course, drawbacks to the administrationof any given pharmaceutical agent. Sometimes, the disadvantages, or“side effects,” are so severe as to preclude administration of aparticular agent at a therapeutically effective dose. Furthermore, manyagents in the same therapeutic class display similar side effectprofiles, meaning that patients either have to forego therapy or sufferfrom varying degrees of side effects associated with the medication ofchoice.

The present invention is directed to an escalating dosing regimen foradministering topiramate alone or in combination with a secondtherapeutic agent that directly or indirectly reduces the side effectsassociated with one or both of the agents administered. By “indirectly”reducing side effects is meant that the second therapeutic agent allowsthe first pharmaceutical agent to be administered at a lower dosewithout compromising therapeutic efficacy, thus resulting dose-dependentunwanted effects.

Topiramate (2,3,4,5-bis-O-(1-methylethylidene)-β-D-fructopyranosesulfamate) is a broad-spectrum neurotherapeutic agent approved by theFDA and the regulatory agencies of many other countries for thetreatment of certain seizure disorders and the prevention of migraineheadaches. E. Faught et al. (1996) Neurology 46:1684-90; Karim et al.(1995) Epilepsia 36 (S4):33; S. K. Sachdeo et al. (1995) Epilepsia 36(S4):33; T. A. Glauser (1999) Epilepsia 40 (S5):S71-80; R. C. Sachdeo(1998) Clin. Pharmacokinet. 34:335-346). There has also been evidencethat topiramate is effective in the treatment of diabetes (U.S. Pat.Nos. 7,109,174 and 6,362,220), neurological disorders (U.S. Pat. No.6,908,902), depression (U.S. Pat. No. 6,627,653), psychosis (U.S. Pat.No. 6,620,819), headaches (U.S. Pat. No. 6,319,903) and hypertension(U.S. Pat. No. 6,201,010). However there have been adverse effectsassociated with the use of topiramate in humans, such as cognitivedulling and word finding difficulties, which can discourage many obesepatients from taking this drug.

As such, there is considerable interest in the development of additionalmethods and compositions for treating obesity and related conditions inwhich the therapeutic efficacy of known therapeutic agents andcompositions are improved. In addition, combination therapy, wherein twoor more active agents are administered in combination, may be employedto decrease the dose of each individual active agent administered andmitigate one or more side effects of the other active agent or agents.Given that the incidence of obesity and conditions caused by or relatedto obesity has reached epidemic proportions, there is an urgent need foreffective methods for the treatment of obesity and/or a relatedcondition, including combination treatments that result in reduction oftoxicity, decreased side effects and effective treatment.

SUMMARY OF THE INVENTION

The present invention provides novel topiramate compositions and methodsfor effecting weight loss, treating obesity, and treating conditionscaused by or associated with excess weight or obesity. The compositionscan contain topiramate as a single active agent but more typicallycontain topiramate in combination with at least one sympathomimeticagent. The term “sympathomimetic agent” is a term of art and refers toagents or compounds that mimic or alter stimulation of the sympatheticnervous system. Exemplary sympathomimetic agents include phentermine andbupropion. Optimally, the topiramate and the sympathomimetic agent arecontained in a single dosage form, which provides for immediate releaseof the sympathomimetic agent and controlled release, e.g., sustainedrelease, delayed release, or both sustained release and delayed release,of the topiramate.

In another aspect of the invention, a controlled release topiramatecomposition is provided that is composed of an effective amount oftopiramate, microcrystalline cellulose, and methylcellulose. Such acomposition will provide for sustained release of the topiramate. Thecomposition, in the form of, for instance, a bead or tablet, may becoated with ethyl cellulose, polyvinyl pyrrolidone, or the like, toprovide for delayed release of the topiramate as well. A sympathomimeticagent is preferably although not necessarily included, and, if present,is preferably in immediate release form.

The present invention features an escalating dosing regimen foradministering topiramate alone or in combination with a sympathomimeticagent, wherein the dosing regimen is in the context of a method foreffecting weight loss, e.g., in a method for treating obesity,overweight, or a condition associated with obesity, or in an alternativemethod, e.g., a method for treating epilepsy, a method for treating animpulse control disorder, or the like. The method involvesadministration of a topiramate composition as described above, whereinthe topiramate is generally although not necessarily administered in acontrolled release composition and/or in combination with asympathomimetic agent. The escalating dosing regimen involvesadministration of an initial daily dosage to an individual for aspecific time period and incrementally increasing the dosage at variousdesignated time points.

The invention also provides a packaged pharmaceutical preparationcomprising topiramate, optionally a sympathomimetic agent as well, andinstructions for administering, e.g., self-administering, the activeagent(s). Generally, the instructions for administration includereference to an escalating dosing regimen wherein a lower daily dosageof topiramate is administered initially, with incremental increases atvarious designated time points thereafter. Ideally, a titration card isprovided that sets forth the recommended dosages for at least fourweeks.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a summary of the plasma concentration of controlledrelease topiramate according to the present invention versus topiramate(Topamax®) in normal obese subjects.

FIG. 2 depicts the mean plasma phentermine concentrations versus timefor subjects administered phentermine in combination with controlledrelease topiramate and phentermine in combination with immediate releasetopiramate (Topamax®).

DETAILED DESCRIPTION OF THE INVENTION Definitions and Nomenclature

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example, “anactive agent” refers not only to a single active agent but also to acombination of two or more different active agents, “a dosage form”refers to a combination of dosage forms as well as to a single dosageform, and the like.

Unless defined otherwise, all technical and scientific terms used hereinhave the meaning commonly understood by one of ordinary skill in the artto which the invention pertains. Specific terminology of particularimportance to the description of the present invention is defined below.

When referring to an active agent, applicants intend the term “activeagent” to encompass not only the specified molecular entity but also itspharmaceutically acceptable, pharmacologically active analogs,including, but not limited to, salts, esters, amides, prodrugs,conjugates, active metabolites, and other such derivatives, analogs, andrelated compounds as will be discussed infra. Therefore, reference to“phentermine,” for example, or “bupropion,” encompasses not onlyphentermine and bupropion per se but also salts and other derivatives ofphentermine and bupropion, e.g., phentermine hydrochloride and bupropionhydrochloride, respectively. It is to be understood that when amounts ordoses are specified, that those amounts or doses refer to the amount ordose of active agent per se and not to a salt or the like. For example,when it is indicated that a dose or amount of phentermine is 7.5 mg,that would correspond to 9.84 phentermine hydrochloride and not 7.5phentermine hydrochloride.

The terms “treating” and “treatment” as used herein refer to reductionin severity and/or frequency of symptoms, elimination of symptoms and/orunderlying cause, and improvement or remediation of damage. In certainaspects, the term “treating” and “treatment” as used herein refer to theprevention of the occurrence of symptoms. In other aspects, the term“treating” and “treatment” as used herein refer to the prevention of theunderlying cause of symptoms associated with obesity, excess weight,and/or a related condition. The phrase “administering to a subject”refers to the process of introducing a composition or dosage form of theinvention into the subject (e.g., a human or other mammalian subject)via an art-recognized means of introduction

By the terms “effective amount” and “therapeutically effective amount”of an agent, compound, drug, composition or combination of the inventionwhich is nontoxic and effective for producing some desired therapeuticeffect upon administration to a subject or patient (e.g., a humansubject or patient).

The term “dosage form” denotes any form of a pharmaceutical compositionthat contains an amount of active agent sufficient to achieve atherapeutic effect with a single administration. When the formulation isa tablet or capsule, the dosage form is usually one such tablet orcapsule. The frequency of administration that will provide the mosteffective results in an efficient manner without overdosing will varywith the characteristics of the particular active agent, including bothits pharmacological characteristics and its physical characteristics,such as hydrophilicity.

The term “controlled release” refers to a drug-containing formulation orfraction thereof in which release of the drug is not immediate, i.e.,with a “controlled release” formulation, administration does not resultin immediate release of the drug into an absorption pool. The term isused interchangeably with “nonimmediate release” as defined inRemington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton,Pa.: Mack Publishing Company, 1995). In general, the term “controlledrelease” as used herein includes sustained release, modified release,and delayed release formulations.

The term “sustained release” (synonymous with “extended release”) isused in its conventional sense to refer to a drug formulation thatprovides for gradual release of a drug over an extended period of time,and that preferably, although not necessarily, results in substantiallyconstant blood levels of a drug over an extended time period. The term“delayed release” is also used in its conventional sense, to refer to adrug formulation which, following administration to a patient provides ameasurable time delay before drug is released from the formulation intothe patient's body.

By “pharmaceutically acceptable” is meant a material that is notbiologically or otherwise undesirable, i.e., the material may beincorporated into a pharmaceutical composition administered to a patientwithout causing any undesirable biological effects or interacting in adeleterious manner with any of the other components of the compositionin which it is contained. When the term “pharmaceutically acceptable” isused to refer to a pharmaceutical carrier or excipient, it is impliedthat the carrier or excipient has met the required standards oftoxicological and manufacturing testing or that it is included on theInactive Ingredient Guide prepared by the U.S. Food and Drugadministration. “Pharmacologically active” (or simply “active”) as in a“pharmacologically active” (or “active”) derivative or analog, refers toa derivative or analog having the same type of pharmacological activityas the parent compound and approximately equivalent in degree. The term“pharmaceutically acceptable salts” include acid addition salts whichare formed with inorganic acids such as, for example, hydrochloric orphosphoric acids, or such organic acids as acetic, oxalic, tartaric,mandelic, and the like. Salts formed with the free carboxyl groups canalso be derived from inorganic bases such as, for example, sodium,potassium, ammonium, calcium, or ferric hydroxides, and such organicbases as isopropylamine, trimethylamine, histidine, procaine and thelike.

As used herein, “subject” or “individual” or “patient” refers to anysubject for whom or which therapy is desired, and generally refers tothe recipient of the therapy to be practiced according to the invention.The subject can be any vertebrate, but will typically be a mammal. If amammal, the subject will in many embodiments be a human, but may also bea domestic livestock, laboratory subject, or pet animal.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges, and are also encompassed within the invention, subjectto any specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

Methods and Formulations of the Invention

The present invention provides novel methods and compositions to effectweight loss and treat obesity, conditions related to excess weight orobesity, diabetes (whether or not related to obesity), and otherconditions and disorders as will be explained infra. According to theU.S. Centers for Disease Control, the clinical definition of beingoverweight (the term being used synonymously herein with the term“excess weight”) is having a body mass index (BMI) between 25.0 and 29.9kg/m; BMI is calculated by multiplying an individual's weight, inkilograms, by height, in meters. The CDC defines obesity as having a BMIof 30 or higher. In one embodiment, the invention provides a method foreffecting weight loss and treating overweight, obesity, and conditionsassociated with excess weight and obesity, and involves administrationof a combination of the sympathomimetic agent phentermine and theanti-convulsant agent topiramate.

Topiramate is an anticonvulsant sulfamate compound that is sold in theUnited States under the trade name Topamax® (Ortho-McNeilPharmaceutical, Inc., Raritan, N.J., U.S.A). Topiramate has beenapproved for use as an antiepileptic agent as an adjuvant therapy forpatients with partial onset seizures or primary generalized tonic-clonicseizures, and for the prevention of migraine headache. See Physician'sDesk Reference, 56th ed. (2002); see also U.S. Pat. No. 4,513,006 toMaryanoff et al. and U.S. Pat. No. 7,351,695 to Almarssoo et al.

“Topiramate” generally refers to the sulfamate-substitutedmonosaccharide having the chemical name2,3,4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate and themolecular formula C12H21NO8S. The structure of the compound isrepresented by Formula (I)

As used herein, the term “topiramate” encompasses2,3,4,5-bis-(O)-(1-methylethylidene)-β-D-fructopyranose sulfamate aswell as individual enantiomers, individual diastereomers, or mixturesthereof. The term “topiramate” as used herein also encompassestopiramate salts as well as polymorphs, solvates (including hydrates andmixed solvates, as well as hydrates of salts), co-crystals (forinstance, with other compounds or other forms of topiramate), amorphous,and anhydrous forms of the compound of Formula (I). Topiramate saltsuseful in conjunction with the present invention, as will be appreciatedfrom the fact that the compound is a sulfamic acid derivative, arepharmaceutically acceptable basic addition salts. Such salts areprepared from bases that provide a pharmaceutically acceptable cationthat associates with the sulfamic acid group of the compound of Formula(I). Suitable pharmaceutically acceptable cations include both organicand inorganic cations, including, without limitation, sodium, sodium,potassium, lithium, magnesium, calcium, aluminum, zinc, procaine,benzathine, chloroprocaine, choline, diethylamine, ethylenediamine,N-methylglucamine, benethamine, clemizole, diethylamine, piperazine,tromethamine, triethylamine, ethanolamine, triethanolamine, arginine,lysine, histidine, tributylamine, 2-amino-2-pentylpropanol,2-amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane,benzylamine, 2-(dimethylamino)ethanol, barium or bismuth counter ions.Particularly preferred cations are sodium, lithium, and potassium. Otherforms of topiramate referenced above may be prepared using methods knownin the art; see, e.g., U.S. Pat. No. 7,351,695. The subject methodsinclude a dosing regimen for the administration of topiramate alone or,more preferably, in combination with a sympathomimetic agent. In certainaspects, the present invention provides a dosing regimen for theadministration of a pharmaceutical composition that includes, e.g.,topiramate in combination with bupropion or phentermine.

In one embodiment of the invention, directed to an escalating dosageregimen, the dosing strategy involves administering to a patient a lowerdaily dosage of topiramate alone or in combination with asympathomimetic agent for a specific period of time and thenincrementally increasing the dosage at various designated time points.

For example, when treating a patient who is overweight or obese, and whomay suffer from a condition associated with or caused by excess weightor obesity, the patient receives a dosage of 15 mg/day to 30 mg/day,e.g., 23 mg/day, of topiramate for 1 week. Next, the patient receives adosage of 35 mg/day to 55 mg/day, e.g., 46 mg/day, of topiramate for asecond week. Thereafter, the patient receives a dosage of 60 mg/day to80 mg/day, e.g., 69 mg/day, of topiramate for a third week, which isfollowed by a final dosage of 85 mg to 125 mg/day, e.g., 92 mg/day oftopiramate for a fourth week.

In another example, when treating a patient for obesity and/or a relatedcondition, the patient receives a dosage of 15 mg/day to 30 mg/day,e.g., 23 mg/day, of topiramate in combination with a dosage of 3.75mg/day of phentermine for 1 week. The patient next receives a dosage of35 mg/day to 55 mg/day, e.g., 46 mg/day, of topiramate in combinationwith a dosage of 7.5 mg/day of phentermine for a second week.Thereafter, the patient receives a dosage of 60 mg/day to 80 mg/day,e.g., 69 mg/day, of topiramate in combination with a dosage of 11.25mg/day of phentermine for a third week which is followed by a finaldosage of 85 mg to 125 mg/day, e.g., 92 mg/day, topiramate incombination with a dosage of 15 mg/day of phentermine for a fourth week.

After the fourth week of administration, the further administration oftopiramate alone or topiramate in combination with phentermine iscarried on indefinitely or, more typically, until a sufficient reductionof symptoms has been achieved. In certain aspects, the final dose of 92mg/day of topiramate alone or in combination with a dosage of 15 mg/dayof phentermine indefinitely or until a sufficient reduction of symptomshas been achieved. In other aspects, the final dose of topiramate aloneor topiramate in combination with phentermine is decreased to theinitial starting dose of the regimen and maintained indefinitely oruntil a sufficient reduction of symptoms has been achieved. In a weightloss regimen, the dosage regimen generally involves continual, i.e.,ongoing, administration, over a significant period of time, e.g., in therange of about 4 weeks to about 67 weeks, depending on the severity ofan individual's weight problem, the amount of weight that should belost, and the rate at which weight is lost.

In another embodiment of the invention, topiramate is administered on anongoing basis, i.e., generally following the escalating dosage regimendescribed above. In either of these methods, i.e., the escalating dosageregimen or an ongoing maintenance dosage regimen, pharmaceuticalcompositions are administered that include an effective amount oftopiramate as the active agent, wherein an “effective amount” oftopiramate is generally an amount that results in a reduction of atleast one pathological parameter associated with obesity, excess weight,and/or a related disorder. In the methods of the invention, e.g., in amethod for effecting weight loss such as in the treatment of obesityand/or a condition related to obesity, an effective amount of topiramateis an amount that is effective to achieve a reduction of at least about10%, at least about 15%, at least about 20%, or at least about 25%, atleast about 30%, at least about 35%, at least about 40%, at least about45%, at least about 50%, at least about 55%, at least about 60%, atleast about 65%, at least about 70%, at least about 75%, at least about80%, at least about 85%, at least about 90%, or at least about 95%,compared to the expected reduction in the parameter, e.g., loss ofweight, in an individual suffering from obesity, excess weight, and/or arelated disorder and not treated with the topiramate compositions.

A suitable daily dose of topiramate is in the range of 10 mg to 1500 mg.For example, 10 mg, 20 mg, 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 180 mg,210 mg, 240 mg, 270 mg, 300 mg, 330 mg, 360 mg, 390 mg, 420 mg, 450 mg,480 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, 1500 mg or the like isadministered to a patient as a daily dosage. In another example, 23 mg,46 mg, 69 mg and 92 mg or the like is administered to a patient as adaily dosage. In some embodiments, the daily dosage of topiramate is inthe range of 10 mg to 150. In certain embodiments, the daily dosage oftopiramate is in the range of 10 mg to 100 mg. Each of theaforementioned “daily dosages” is generally although not necessarilyadministered as a single daily dose.

The patient may receive a specific dosage of topiramate over a period ofweeks, months, or years, e.g., 1 week, 2 weeks, 3 weeks, 1 month, 2months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5years, and the like.

Aspects of the invention provide a topiramate monotherapy or combinationtherapy in which the subject topiramate formulation is effective whenadministered at an initial dose as low as 10-23 mg. In certain aspects,the topiramate formulation is effective at a dose of approximately 20mg. The novel topiramate formulations of the present invention have alower maximum concentration (Cmax) without decreasing total drugexposure defined by the area under the concentration-time curve (AUC).Further, the novel topiramate formulations of the present invention havea delay in time after administration of a drug when the maximum plasmaconcentration is reached (Tmax) by six to eight hours. As depicted inFIG. 1, drug exposure as measured by AUC for the control release (CR)formulation capsule is the same as the 100 mg of immediate releasetopiramate (Topamax®) tablet despite a 20% reduction in the Cmax.Therefore, this formulation is capable of reducing the Cmax which wouldreduce side effects without compromising the efficacy of the treatment,since the AUC is the same. This reduction in Cmax is preferred astopiramate can be sedating and a delay in the time to reach maximumplasma concentration to the late afternoon or evening time would improvethe tolerability of the drug.

As such, the effective amount of topiramate is decreased, therebyfurther reducing any toxicity or harmful side effects in the patient.The amount of topiramate administered to the patient is less than anamount that would cause toxicity in the patient. In certain embodiments,the amount of the compound that is administered to the patient is lessthan the amount that causes a concentration of the compound in thepatient's plasma to equal or exceed the toxic level of the compound. Theoptimal amount of the compound that should be administered to thepatient in the practice of the present invention will depend on theindividual as well as the severity of the individual's symptoms.

Depending on the intended mode of administration, the pharmaceuticalformulation may be a solid, semi-solid or liquid, such as, for example,a tablet, a capsule, a caplet, a liquid, a suspension, an emulsion, asuppository, granules, pellets, beads, a powder, or the like, preferablyin unit dosage form suitable for single administration of a precisedosage. Suitable pharmaceutical compositions and dosage forms may beprepared using conventional methods known to those in the field ofpharmaceutical formulation and described in the pertinent texts andliterature, e.g., in Remington: The Science and Practice of Pharmacy(Easton, Pa.: Mack Publishing Co., 1995). Oral administration andtherefore oral dosage forms are generally preferred, and includetablets, capsules, caplets, solutions, suspensions and syrups, and mayalso comprise a plurality of granules, beads, powders, or pellets thatmay or may not be encapsulated. Preferred oral dosage forms are capsulesand tablets, particularly controlled release capsules and tablets, asnoted above.

As noted above, it is especially advantageous to formulate compositionsof the invention in unit dosage form for ease of administration anduniformity of dosage. The term “unit dosage forms” as used herein refersto physically discrete units suited as unitary dosages for theindividuals to be treated. That is, the compositions are formulated intodiscrete dosage units each containing a predetermined, “unit dosage”quantity of an active agent calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. The specifications of unit dosage forms of the invention aredependent on the unique characteristics of the active agent to bedelivered. Dosages can further be determined by reference to the usualdose and manner of administration of the ingredients. It should be notedthat, in some cases, two or more individual dosage units in combinationprovide a therapeutically effective amount of the active agent, e.g.,two tablets or capsules taken together may provide a therapeuticallyeffective dosage of topiramate, such that the unit dosage in each tabletor capsule is approximately 50% of the therapeutically effective amount.

Tablets may be manufactured using standard tablet processing proceduresand equipment. Direct compression and granulation techniques arepreferred. In addition to the active agent, tablets will generallycontain inactive, pharmaceutically acceptable carrier materials such asbinders, lubricants, disintegrants, fillers, stabilizers, surfactants,coloring agents, and the like.

Capsules are also preferred oral dosage forms, in which case the activeagent-containing composition may be encapsulated in the form of a liquidor solid (including particulates such as granules, beads, powders orpellets). Suitable capsules may be either hard or soft, and aregenerally made of gelatin, starch, or a cellulosic material, withgelatin capsules preferred. Two-piece hard gelatin capsules arepreferably sealed, such as with gelatin bands or the like. See, forexample, Remington: The Science and Practice of Pharmacy, cited earlierherein, which describes materials and methods for preparing encapsulatedpharmaceuticals.

Oral dosage forms, whether tablets, capsules, caplets, or particulates,can, if desired, be formulated so as to provide for controlled releaseof topiramate, and in a preferred embodiment, the present formulationsare controlled release oral dosage forms. Generally, the dosage formsprovide for sustained release, i.e., gradual, release of topiramate,from the dosage form to the patient's body over an extended time period,typically providing for a substantially constant blood level of theagent over a time period in the range of about 4 to about 12 hours,typically in the range of about 6 to about 10 hours or 6 to about 8hours. Release of the topiramate may also be delayed; that is, there isa time lag between administration and the start of topiramate release.In this way, for instance, an individual will not experience sleepinessor other side effects of topiramate during the school or work day.Preferred dosage forms thus involve sustained release of the topiramate,delayed release of the topiramate, or both sustained and delayed releaseof the topiramate.

Generally, as will be appreciated by those of ordinary skill in the art,sustained release dosage forms are formulated by dispersing the activeagent within a matrix of a gradually hydrolyzable material such as ahydrophilic polymer, or by coating a solid, drug-containing dosage formwith such a material. Hydrophilic polymers useful for providing asustained release coating or matrix include, by way of example:cellulosic polymers such as hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethylcellulose, cellulose acetate, and carboxymethylcellulose sodium; acrylicacid polymers and copolymers, preferably formed from acrylic acid,methacrylic acid, acrylic acid alkyl esters, methacrylic acid alkylesters, and the like, e.g. copolymers of acrylic acid, methacrylic acid,methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethylmethacrylate; and vinyl polymers and copolymers such as polyvinylpyrrolidone e.g., Povidone K30, polyvinyl acetate, and ethylene-vinylacetate copolymer. Preferred sustained release polymers herein includethose available as “Methocel” polymers from Dow Chemical, particularlythe methylcellulose ether polymers in the Methocel™ A group, having aviscosity grade of about 4,000 cps and a methoxyl content of about 27.5%to 31.5%, e.g., Methocel™ A15LV, Methocel™ A15C, and Methocel™ A4M.

When sustained release preparations are prepared, tablets, granules,powder, capsules, and the like can be produced according to aconventional method after adding excipient, and as necessary, binder,disintegrating agent, lubricant, coloring agent, taste-modifying agent,flavoring agent, and the like. These additives may be ones generallyused in the field, and for example, lactose, sodium chloride, glucose,starch, microcrystalline cellulose, and silicic acid as the excipient,water, ethanol, propanol, simple syrup, gelatin solution, hydroxypropylcellulose, methyl cellulose, ethyl cellulose, shellac, calciumphosphate, and polyvinylpyrrolidone as the binder, agar powder, sodiumhydrogen carbonate, sodium lauryl sulfate, and stearic acidmonoglyceride as the disintegrating agent, purified talc, stearic acidsalt, borax, and polyethylene glycol as the lubricant, (3-carotene,yellow iron sesquioxide, and caramel as the coloring agent, andsaccharose and orange peel as the taste-modifying agent can be listed asexamples. It should be noted that various grades of microcrystallinecellulose are preferred fillers herein, e.g., Avicel® PH101, Avicel®PH102, and Avicel® PH200 (FMC), with particle sizes of about 50 microns,100 microns, and 190 microns, respectively. Microcrystalline cellulosehaving a particle size in the range of about 50 microns to 200 micronsis preferred herein.

The dosage forms may also be provided with a delayed release coating,e.g., composed of an acrylate and/or methacrylate copolymers. Examplesof such polymers are those available under the trade name “Eudragit”from Rohm Pharma (Germany). The Eudragit series E, L, S, RL, RS, and NEcopolymers are available as solubilized in organic solvent, in anaqueous dispersion, or as a dry powder. Preferred acrylate polymers arecopolymers of methacrylic acid and methyl methacrylate, such as theEudragit L and Eudragit S series polymers. Other preferred Eudragitpolymers are cationic, such as the Eudragit E, RS, and RL seriespolymers. Eudragit E100 and E PO are cationic copolymers ofdimethylaminoethyl methacrylate and neutral methacrylates (e.g., methylmethacrylate), while Eudragit RS and Eudragit RL polymers are analogouspolymers, composed of neutral methacrylic acid esters and a smallproportion of trimethylammonioethyl methacrylate.

In a specific embodiment, controlled release topiramate beads for oraladministration, e.g., by incorporation in an orally administrablecapsule or compaction into an orally administrable tablet, are madeusing an extrusion spheronization process to produce a matrix corecomprised of: topiramate, 40.0% w/w; microcrystalline cellulose, e.g.,Avicel® PH102, 56.5% w/w; and methylcellulose, e.g., Methocel™ A15 LV,3.5% w/w. The topiramate cores are then coated with ethyl cellulose,5.47% w/w and Povidone K30: 2.39% w/w. As will be described in detailinfra, beads of a second active agent, e.g., a sympathomimetic agent,may also be prepared and incorporated into the capsule. For instance,phentermine or bupropion beads having an immediate release drug coatingon sugar spheres or analogous non-active cores may be employed. Bothsets of beads may then be encapsulated into one capsule.

Preparations according to this invention for parenteral administrationinclude sterile aqueous and nonaqueous solutions, suspensions, andemulsions. Injectable aqueous solutions contain the active agent inwater-soluble form. Examples of nonaqueous solvents or vehicles includefatty oils, such as olive oil and corn oil, synthetic fatty acid esters,such as ethyl oleate or triglycerides, low molecular weight alcoholssuch as propylene glycol, synthetic hydrophilic polymers such aspolyethylene glycol, liposomes, and the like. Parenteral formulationsmay also contain adjuvants such as solubilizers, preservatives, wettingagents, emulsifiers, dispersants, and stabilizers, and aqueoussuspensions may contain substances that increase the viscosity of thesuspension, such as sodium carboxymethyl cellulose, sorbitol, anddextran. Injectable formulations are rendered sterile by incorporationof a sterilizing agent, filtration through a bacteria-retaining filter,irradiation, or heat. They can also be manufactured using a sterileinjectable medium. The active agent may also be in dried, e.g.,lyophilized, form that may be rehydrated with a suitable vehicleimmediately prior to administration via injection.

The active agents may also be administered through the skin usingconventional transdermal drug delivery systems, wherein the active agentis contained within a laminated structure that serves as a drug deliverydevice to be affixed to the skin. In such a structure, the drugcomposition is contained in a layer, or “reservoir,” underlying an upperbacking layer. The laminated structure may contain a single reservoir,or it may contain multiple reservoirs. In one embodiment, the reservoircomprises a polymeric matrix of a pharmaceutically acceptable contactadhesive material that serves to affix the system to the skin duringdrug delivery. Alternatively, the drug-containing reservoir and skincontact adhesive are present as separate and distinct layers, with theadhesive underlying the reservoir which, in this case, may be either apolymeric matrix as described above, or it may be a liquid or hydrogelreservoir, or may take some other form. Transdermal drug deliverysystems may in addition contain a skin permeation enhancer.

In addition to the formulations described previously, the active agentmay be formulated as a depot preparation for controlled release of theactive agent, preferably sustained release over an extended time period.These sustained release dosage forms are generally administered byimplantation (e.g., subcutaneously or intramuscularly or byintramuscular injection).

Although the present compositions will generally be administered orally,parenterally, transdermally, or via an implanted depot, other modes ofadministration are suitable as well. For example, administration may betransmucosal, e.g., rectal or vaginal, preferably using a suppositorythat contains, in addition to the active agent, excipients such as asuppository wax. Formulations for nasal or sublingual administration arealso prepared with standard excipients well known in the art. Thepharmaceutical compositions of the invention may also be formulated forinhalation, e.g., as a solution in saline, as a dry powder, or as anaerosol.

In another embodiment, the methods of the invention, i.e., theescalating dosage regimen or ongoing maintenance dosing, involveadministration of a combination of topiramate and a sympathomimeticagent.

Sympathomimetic agents for use in the present invention and theirgeneral clinical uses or effects are set forth in Table 1.

TABLE 1 Sympathomimetic Agents and Clinical Uses Thereof Generalstructure: Main Clinical Uses Ring (Receptor ® Receptor Agent nameSubstituents(s) R^(a) R^(β) R⁷ A N P V B C CNS, 0 Bupropion 3-Cl ═O CH₃C(CH₃)₃ Phenylethylamine H H H Epinephrine 3-OH, 4-OH OH H CH₃ A, P, VB, C Norepinephrine 3-OH, 4-OH OH H H P Epinine 3-OH, 4-OH H H CH₃Dopamine 3-OH, 4-OH H H H P Dobutamine 3-OH, 4-OH H H 1* C Nordefrin3-OH, 4-OH OH CH₃ H V Ethylnorepinephrine 3-OH, 4-OH OH CH₂CH₃ H BIsoproterenol 3-OH, 4-OH OH H CH(CH₃)₂ B, C Protokylol 3-OH, 4-OH OH H2* B Isoetharine 3-OH, 4-OH OH CH₂CH₃ CH(CH₃)₂ B Metaproterenol 3-OH,5-OH OH H CH(CH₃)₂ B Terbutaline 3-OH, 5-OH OH H C(CH₃)₃ B Metaraminol3-OH OH CH₃ H P Phenylephrine 3-OH OH H CH₃ N, P Tyramine 4-OH H H HHydroxyamphetamine 4-OH H CH₃ H N, P C Methoxyphenamine 2-OCH₃ H CH₃ CH₃B Methoxamine 2-OCH₃, 5-OCH₃ OH CH₃ H P Albuterol 3-CH₂OH, 4-OH OH HC(CH₃)₃ B Amphetamine H CH₃ H CNS, 0 Methamphetamine H CH₃ CH₃ P CNS, 0Benzphetamine H CH₃ —NHR⁷ is 0 replaced with 3* Ephedrine OH CH₃ CH₃ N,P B, C Phenylpropanolamine OH CH₃ H N Mephentermine H —CHR^(β)— is CH₃N, P replaced with 4* Phentermine H ″ H 0 Chlorphentermine 4-Cl H ″ H 0Fenfluramine 3-CF₃ H CH₃ C₂H₅ 0 Propylhexedrine 5*: phenyl ring H CH₃CH₃ N is replaced with cyclohexyl Diethylpropion 6*: The substituent atthe 1- 0 position is replaced with 6, below. Phenmetrazine 7*: Thesubstituent at the 1- 0 position is replaced with 7, below.Phendimetrazine 8*: The substituent at the 1- 0 position is replacedwith 8, below.

*6:

(Activity A = Allergic reaction (includes ® action) N = Nasaldecongestion P = Pressor (may include ® action) V = Other localvasoconstriction (e.g. in local anesthesia) ® Activity B =Bronchodilator C = Cardiac CNS = Central nervous system 0 = Anorectic*Numbers bearing an asterisk refer to the substituents numbered in thebottom rows of the table; substituent 5 replaces the phenyl rings, and6, 7 and 8 are attached directly to the phenyl ring, replacing theethylamine side chain. ^(†)The < and ® in the prototype formula refer topositions of the C atoms in the ethylamine side chain.

In certain embodiments, the sympathomimetic agent is phentermine or aphentermine-like compound. As defined herein, a “phentermine-likecompound” is a compound structurally related to phentermine (e.g., ananalog or derivative) which maintains an anorectic activity similar tothat of phentermine. One phentermine-like compound is chlorphentermine.In yet another embodiment, the sympathomimetic agent is amphetamine oran amphetamine-like compound. As used herein, an “amphetamine-likecompound” is a compound structurally related to amphetamine (e.g., ananalog or derivative) which maintains an anorectic effect ofamphetamine. In yet another embodiment, the sympathomimetic agent isphenmetrazine or a phenmetrazine-like compound. As defined herein, a“phenmetrazine-like compound” is a compound structurally related tophenmetrazine (e.g., an analog or derivative) which maintains ananorectic effect of phenmetrazine. One phenmetrazine-like compound isphendimetrazine. Analogs and/or derivatives of the compounds of thepresent invention can be tested for their ability to suppress appetite(e.g., suppress food intake) in a subject (e.g., a mammalian subject).

In other embodiments, the sympathomimetic agent is bupropion or abupropion-like compound. As defined herein, a “bupropion-like compound”is a compound structurally related to bupropion (e.g., an analog orderivative) which maintains an anti-depressive activity similar to thatof bupropion.

In an exemplary embodiment, the sympathomimetic agent is selected frombupropion, amphetamine, methamphetamine, benzphetamine,phenylpropanolamine, phentermine, chlorphentermine, diethylpropion,phenmetrazine, and phendimetrazine (as set forth in Table 1).

In one embodiment, the sympathomimetic agent is phentermine. It is alsowithin the scope of the present invention to utilize othersympathomimetic agents including pseudoephedrine (a stereoisomer ofephedrine), methylphenidate, dexmethylphenidate, tuaminoheptane, andother CNS stimulants including, for example, caffeine and bupropion.

The selection of appropriate dosages for the drugs used in combinationtherapy according to the present invention can be determined andoptimized by the skilled artisan, e.g., by observation of the patient,including the patient's overall health, the response to the combinationtherapy, and the like. Optimization may be necessary if it is determinedthat a patient is not exhibiting the desired therapeutic effect or,conversely, if the patient is experiencing undesirable or adverse sideeffects that are too many in number or are of troublesome severity.

Although the dosage used will vary depending on the clinical goals to beachieved, a suitable daily dose range for the sympathomimetic agent isgenerally in the range of 2 mg to 1500 mg, administered to a patientover an ongoing time period. For example, 2 mg, 4 mg, 10 mg, 20 mg, 30mg, 60 mg, 90 mg, 120 mg, 150 mg, 180 mg, 210 mg, 240 mg, 270 mg, 300mg, 330 mg, 360 mg, 390 mg, 420 mg, 450 mg, 480 mg, 500 mg, 600 mg, 800mg, 1000 mg, 1200 mg, 1500 mg or the like is administered to a patientas a daily dosage, which may be a single daily dosage. In anotherexample, 3.75 mg, 7.5 mg, 11.75 mg, 15 mg or the like is administered toa patient as a daily dosage, which, again, may be a single daily dosage.

In one embodiment, each component of the combination (e.g., (i)topiramate, and (ii) a sympathomimetic drug) is prescribed at a dosethat is below the typically described dose for each component as amonotherapy. The components may be prescribed separately or as acombination dosage. In one embodiment, each component of the combination(e.g., (i) topiramate, and (ii) a sympathomimetic drug) is prescribed ata dose that is above the typically described dose for each component asa monotherapy. The components may be prescribed separately or as acombination dosage.

In another embodiment, the prescribed dosage of the sympathomimetic drugis above the typically described dose for monotherapy, and topiramate isprescribed at a dosage that is at or below the typically described dosefor monotherapy. In another embodiment, the prescribed dosage of thesympathomimetic drug is at or below the typically described dose formonotherapy, and topiramate is prescribed at a dosage that is above thetypically described dose for monotherapy.

In certain embodiments, when phentermine is the sympathomimetic agent,phentermine may be, for example, administered at a daily dosage, e.g., asingle daily dosage, in the range of 2 mg to 60 mg. In one aspect, thephentermine is administered at a daily dosage, e.g., a single dailydosage, in the range of 2 mg to 30 mg. In another aspect, thephentermine is administered at a daily dosage, e.g., a single dailydosage, in the range of 2 mg to 15 mg.

In certain embodiments, when bupropion is the sympathomimetic agent,bupropion may be, for example, administered at a daily dosage, e.g., asingle daily dosage, in the range of 50 mg to 400 mg, more typically inthe range of 50 mg to 200 mg.

The method of administration of pharmaceutical combinations of theinvention will depend, in particular, on the type of sympathomimeticagent used. Topiramate and the sympathomimetic agent may be administeredtogether in the same composition or simultaneously or sequentially intwo separate compositions. Also, one or more sympathomimetic agents maybe administered to a subject or patient either in the form of atherapeutic composition or in combination, e.g., in the form of one ormore separate compositions administered simultaneously or sequentially.The schedule of administration will be dependent on the type ofsympathomimetic agent(s) chosen. For example, a sympathomimetic agentcan have a stimulant effect and the degree of the stimulant effect mayvary depending on the sympathomimetic agent chosen. A sympathomimeticagent having a significant stimulant effect would preferably beadministered earlier in the day than would a sympathomimetic agenthaving a lesser stimulant effect. Topiramate, which typically has atleast some sedative effect even at lower doses, may be administeredlater in the day than administration of a compound having a lessersedative effect.

In one embodiment, topiramate is administered in a controlled releaseform, i.e., in sustained release and/or delayed release form, preferablyboth, and phentermine is administered in an immediate release form. Assuch, the phentermine may be taken in the morning because the drug is astimulant as well as an appetite suppressant. In this embodiment,topiramate may be taken later in the day than the phentermine.Preferably, the patient takes the topiramate just before dinner or laterin the evening because the drug is sedating.

In yet another embodiment, topiramate is administered in a controlledrelease form, i.e., in sustained release and/or delayed release form,and bupropion is administered in an immediate release form. As such, thebupropion may be taken in the morning because the drug is a stimulant aswell as an appetite suppressant. In this embodiment, topiramate may betaken later in the day than the bupropion. Preferably, the patient takesthe topiramate just before dinner or later in the evening because thedrug is sedating.

As described supra, a controlled release dosage form of the inventionwherein combination therapy is indicated can be a capsule containingcontrolled release topiramate beads and immediate release phenterminebeads, bupropion beads, or the like. The topiramate beads may be madeusing an extrusion spheronization process to produce a matrix corecomprised of: topiramate, 40.0% w/w; microcrystalline cellulose, e.g.,Avicel® PH102, 56.5% w/w; and methylcellulose, e.g., Methocel™ A15 LV,3.5% w/w. The topiramate cores are then coated with ethyl cellulose,5.47% w/w and Povidone K30: 2.39% w/w. The phentermine beads, bupropionbeads, or the like, are composed of an immediate release drug coating onsugar spheres or analogous non-active cores. Both sets of beads are thenencapsulated into one capsule.

In certain embodiments, the phentermine beads may be provided with acontrolled release drug coating on sugar spheres or other non-activecores. In other aspects, the phentermine beads may be coated onto thecontrolled release topiramate beads.

In combination therapy, then, a preferred method of administrationinvolves simultaneous administration of the two active agents, in asingle composition or in two discrete compositions each containing oneof the active agents. The method of administration may also involveadministration of the two active agents at different times of day, withthe sympathomimetic agent generally administered earlier in the day andthe topiramate generally administered later in the day. Normally,however, the two agents are administered simultaneously using one ormore dosage forms that provide for immediate release of thesympathomimetic agent and controlled release of the topiramate. In anexemplary embodiment, the sympathomimetic agent and the topiramate areadministered in a single dosage form that provides for immediate releaseof the sympathomimetic agent and sustained release and/or delayedrelease, preferably both sustained release and delayed release, of thetopiramate. Such dosage forms may be coated cores or encapsulated beads,as described above, or they may be tablets, wherein, for example, thetablets contain at least two discrete segments, at least one of whichcontains the sympathomimetic agent such as phentermine or bupropion inimmediate release form, and another of which contains topiramate incontrolled release form.

Indications

Conditions of particular interest for which the invention finds utilityinclude overweight, obesity, and conditions often associated with and/orcaused by excess weight and obesity. Topiramate compositions andcombinations administered according to the dosage regimens providedherein give rise to significant therapeutic effects and reduced adverseeffects, making these pharmaceutical compositions extremely effectivetherapeutics, especially in the treatment of overweight, obesity, and/orrelated conditions, including conditions associated with and/or causedby excess weight or obesity per se. Subjects suitable for treatment withthe subject combination therapy treatment regimen thus includeindividuals suffering from conditions associated with obesity, suchconditions including, without limitation:

-   -   diabetes, insulin resistance, and impaired glucose tolerance;    -   respiratory problems such as pulmonary hypertension, asthma, and        shortness of breath;    -   gallbladder disease;    -   dyslipidemia, e.g., high cholesterol, high levels of        triglycerides, etc.;    -   osteoarthritis and other orthopedic problems;    -   reflux esophagitis;    -   adverse conditions related to sleep, including sleep apnea and        loud snoring;    -   menstrual irregularities, infertility, and complications in        pregnancy;    -   gout;    -   high blood pressure, i.e., hypertension;    -   cardiovascular problems such as coronary artery disease and        other heart trouble;    -   muscular dystrophy;    -   stroke, particularly thrombotic stroke and deep vein thrombosis        (DVT);    -   migraines;    -   metabolic disorders such as hypoalphalipoproteinemia, familial        combined hyperlipidemia, and Syndrome X, including        insulin-resistant Syndrome X; and    -   colon, rectal, renal, esophageal, gallbladder, pancreatic,        prostate, breast, uterine, ovarian, endometrial, and cervical        cancers.

Higher body weights are also associated with increases in all-causemortality. Most or all of these problems are relieved or improved bypermanent significant weight loss. Longevity is likewise significantlyincreased by permanent significant weight loss.

Diabetes mellitus is very commonly seen in obese individuals, and isassociated with continuous and pathologically elevated blood glucoseconcentration. It is one of the leading causes of death in the UnitedStates and is responsible for about 5% of all mortality. Diabetes isdivided into two major sub-classes: Type I, also known as juvenilediabetes, or Insulin-218299437 Dependent Diabetes Mellitus (IDDM); andType II, also known as adult onset diabetes, or Non-Insulin-DependentDiabetes Mellitus (NIDDM).

According to the American Diabetes Association, there are over onemillion juvenile diabetics in the United States. Type I Diabetes is aform of autoimmune disease. Autoantibodies produced by the patientscompletely or partially destroy the insulin producing cells of thepancreas. Juvenile diabetics must, therefore, receive exogenous insulinduring their lifetime. Without treatment, excessive acidosis,dehydration, kidney damage, and death may result. Even with treatment,complications such as blindness, atherosclerosis, and impotence canoccur.

There are more than five million Type II (adult onset) diabeticsdiagnosed in the United States. Type II disease usually begins duringmiddle age; the principal cause is now known to be overweight andobesity. In Type II diabetics, rising blood glucose levels after mealsdo not properly stimulate insulin production by the pancreas.Additionally, peripheral tissues are generally resistant to the effectsof insulin. The resulting high blood glucose levels (hyperglycemia) cancause extensive tissue damage. Type II diabetics are often referred toas insulin resistant. They often have higher than normal plasma insulinlevels (hyperinsulinemia) as the body attempts to overcome its insulinresistance. Some researchers now believe that hyperinsulinemia may be acausative factor in the development of high blood pressure, high levelsof circulating low density lipoproteins (LDLs), and lower than normallevels of the beneficial high density lipoproteins (HDLs). Whilemoderate insulin resistance can be compensated for in the early stagesof Type II diabetes by increased insulin secretion, in more advanceddisease states insulin secretion is also impaired.

Insulin resistance and hyperinsulinemia have also been linked with twoother metabolic disorders that pose considerable health risks: impairedglucose tolerance and metabolic obesity. Impaired glucose tolerance ischaracterized by normal glucose levels before eating, with a tendencytoward elevated levels (hyperglycemia) following a meal. According tothe World Health Organization, approximately 11% of the U.S. populationbetween the ages of 20 and 74 are estimated to have impaired glucosetolerance. These individuals are considered to be at higher risk fordiabetes and coronary artery disease.

Obesity may also be associated with insulin resistance. A causal linkageamong obesity, impaired glucose tolerance, and Type II diabetes has beenproposed, but a physiological basis has not yet been established. Someresearchers believe that impaired glucose tolerance and diabetes areclinically observed and diagnosed only later in the disease processafter a person has developed insulin resistance and hyperinsulinemia.

Insulin resistance is frequently associated with hypertension, coronaryartery disease (arteriosclerosis), and lactic acidosis, as well asrelated disease states. The fundamental relationship between thesedisease states, and a method of treatment, has not been established.

Hypertension is another condition that is frequently seen in obeseindividuals, and occurs when the blood pressure inside the largearteries is chronically elevated. Hypertension affects about 50 millionpeople in the United States alone. It is more common as people growolder and is both more common and more serious in African Americans.Most cases of hypertension are of unknown etiology. It is known that thetendency to develop hypertension can be inherited. Environment alsoplays a very important role in hypertension. For example, hypertensionmay be avoided by keeping body weight under control, keeping physicallyfit, eating a healthy diet, limiting alcohol intake, and avoidingmedications that might increase blood pressure. Other less common causesof hypertension include disorders of the kidneys or endocrine glands.Hypertension has been called “the silent killer” because it has nospecific symptoms and yet can lead to death. People with untreatedhypertension are much more likely to die from or be disabled bycardiovascular complications such as strokes, heart attacks, heartfailure, heart rhythm irregularities, and kidney failure, than peoplewho have normal blood pressure.

Current treatments for hypertension include lifestyle changes (diet,exercise, nonsmoking, etc.) as well as drug therapy. The major classesof medications currently used to treat hypertension include adrenergicneuron antagonists (which are peripherally acting), alpha adrenergicagonists (which are centrally acting), alpha adrenergic blockers, alphaand beta blockers, angiotensin II receptor blockers, angiotensinconverting enzyme (ACE) inhibitors, beta adrenergic blockers, calciumchannel blockers, thiazides (benzothiadiazine derivatives) and relateddiuretics, and vasodilators (which act by direct relaxation of vascularsmooth muscles).

A particularly serious hypertensive disorder is primary pulmonaryhypertension, also known as idiopathic pulmonary hypertension. This is acondition in which the blood pressure in the pulmonary arteries isabnormally high in the absence of other diseases of the heart or lungs.The cause of primary pulmonary hypertension is unknown. Pulmonaryhypertension develops in response to increased resistance to blood flow.Narrowing of the pulmonary arterioles occurs and the right side of theheart becomes enlarged due to the increased work of pumping bloodagainst the resistance. Eventually, progressive heart failure develops.Currently, there is no known cure for primary pulmonary hypertension.Treatment is primarily directed towards controlling the symptoms,although some success has occurred with the use of vasodilators. Othermedications used to treat the symptoms of primary pulmonary hypertensioninclude diuretics and calcium channel blockers. Typically, as thedisease progresses, oxygen is often required. In certain cases, aheart-lung transplant may be indicated for certain suitable candidates,although the availability of donor organs continues to be extremelylimited. Unfortunately, primary pulmonary hypertension is a progressivedisease, usually leading to congestive heart failure and respiratoryfailure.

Secondary pulmonary hypertension is a serious disorder that arises as acomplication of other conditions such as, for example, scleroderma.Treatments are similar as those for primary pulmonary hypertension and,unfortunately, the prognosis is the same as well.

Other respiratory disorders that are frequently seen in obeseindividuals include asthma and shortness of breath, both of whichconditions are often alleviated by weight loss.

With respect to adverse conditions and disorders associated with sleep,sleep apnea is perhaps the most concerning. Sleep apnea is classified aseither obstructive sleep apnea, the more common form that occurs whenthroat muscles relax, or central sleep apnea, which occurs when thebrain doesn't send proper signals to the muscles that control breathing.Additionally, some people have mixed sleep apnea, which is a combinationof both obstructive and central sleep apneas. Sleep apnea literallymeans “cessation of breath.” It is characterized by repetitive episodesof upper airway obstruction that occur during sleep, usually associatedwith a reduction in blood oxygen saturation. In other words, the airwaybecomes obstructed at several possible sites. The upper airway can beobstructed by excess tissue in the airway, large tonsils, and a largetongue and usually includes the airway muscles relaxing and collapsingwhen asleep. Another site of obstruction can be the nasal passages.Sometimes the structure of the jaw and airway can be a factor in sleepapnea.

The signs and symptoms of obstructive and central sleep apneas overlap,sometimes making the type of sleep apnea more difficult to determine.The most common signs and symptoms of obstructive and central sleepapneas include: excessive daytime sleepiness (hypersomnia); loudsnoring; observed episodes of breathing cessation during sleep; abruptawakenings accompanied by shortness of breath; awakening with a drymouth or sore throat; morning headache; and/or difficulty staying asleep(insomnia). Disruptive snoring may be a more prominent characteristic ofobstructive sleep apnea, while awakening with shortness of breath may bemore common with central sleep apnea.

Sleep apnea is a progressive condition and can be very serious; it is apotentially life-threatening condition that requires immediate medicalattention. The risks of undiagnosed obstructive sleep apnea includeheart attacks, strokes, high blood pressure, heart disease, irregularheartbeat, and impotence. In addition, obstructive sleep apnea causesdaytime sleepiness that can result in accidents, lost productivity andinterpersonal relationship problems. The severity of the symptoms may bemild, moderate, or severe.

Sleep apnea is diagnosed utilizing a sleep test, called polysomnographybut treatment methodologies differ depending on the severity of thedisorder. Mild Sleep Apnea is usually treated by some behavioralchanges; losing weight and sleeping on one's side are often recommended.There are oral mouth devices (that help keep the airway open) that mayhelp to reduce snoring in three different ways. Some devices (1) bringthe jaw forward or (2) elevate the soft palate or (3) retain the tongue(from falling back in the airway and blocking breathing).

Moderate to severe sleep apnea is usually treated with a continuouspositive airway pressure (C-PAP). C-PAP is a machine that blows air intoyour nose via a nose mask, keeping the airway open and unobstructed. Formore severe apnea, there is a Bi-level (Bi-PAP) machine. The Bi-levelmachine is different in that it blows air at two different pressures.When a person inhales, the pressure is higher and in exhaling, thepressure is lower.

Some people have facial deformities that may cause the sleep apnea. Itsimply may be that their jaw is smaller than it should be or they couldhave a smaller opening at the back of the throat. Some people haveenlarged tonsils, a large tongue, or some other tissues partiallyblocking the airway. Fixing a deviated septum may help to open the nasalpassages. Removing the tonsils and adenoids or polyps may help also.Children are much more likely to have their tonsils and adenoidsremoved. Surgical procedures, such as tracheostomy,uvulopalatopharyngoplasty (UPPP), laser assisted uvuloplasty (LAUD),somnoplasty, and mandibular myotomy are often required to effectivelytreat sleep apnea. Weight loss, however, particularly in an obeseperson, can significantly alleviate sleep apnea and other sleep-relatedadverse conditions such as loud snoring and the like.

Relatively recently, a connection between obesity and the occurrence orincreased incidence of migraine headaches has been noted. Migraineheadaches begin with mild pain, which increases in intensity over ashort period of time. There are two major types of migraines. The commonmigraine affects 80-85% of migraine sufferers and classical migrainewith aura affects 15% of migraine sufferers. Symptoms associated withmigraines include headaches, psychological symptomology such asirritability, depression, fatigue, drowsiness, restlessness;neurological symptoms such as photophobia, phonophobia orgastrointestinal symptoms such as change in bowel habit, change of foodintake or urinary symptoms such as urinary frequency, auras which areneurological deficits and can be a variety of deficits for the migrainepopulation but in the individual is usually stereotyped. These deficitsmay be visual scotoma or visual designs, hemiplegia, migratingparaesthesia, dysarthria, dysphasia, or déjà vu. The headache is usuallyaccompanied by light or sound sensitivity, photophobia or phonophobia,irritability and impaired concentration. For those individuals whosemigraine headaches are caused by or exacerbated by obesity, treatmentaccording to the methodology of the present invention can be effective.

Other indications for which the present invention is readily adaptedinclude epilepsy and certain psychiatric indications such as impulsecontrol disorders.

Topiramate has long been known as an anti-epileptic agent. At dosagespreviously required or believed to be required for efficacy, however,topiramate therapy resulted in significant side effects, as notedelsewhere herein. The present invention, according to which topiramatedosage may be reduced by concomitant administration of phentermine,significantly reduces those side effects of topiramate, most if not allof which are dose-related.

Among psychiatric indications, depression is particularly common.“Depression,” as is well known, is manifested by a combination ofsymptoms that interfere with the ability to work, study, sleep, eat, andenjoy once pleasurable activities. Depression includes major depression,especially refractory depression, bipolar depression, and thedegeneration associated with depression. Symptoms of depression includepersistent sad, anxious, or “empty” mood, feelings of hopelessness,pessimism, feelings of guilt, worthlessness, helplessness, loss ofinterest or pleasure in hobbies and activities that were once enjoyed,including sex, decreased energy, fatigue, being “slowed down”,difficulty concentrating, remembering, making decisions, insomnia,early-morning awakening, or oversleeping, appetite and/or weight loss orovereating and weight gain, thoughts of death or suicide; suicideattempts, restlessness, irritability, persistent physical symptoms thatdo not respond to treatment, such as headaches, digestive disorders, andchronic pain.

Other psychiatric disorders may also be treated using the compositionsand methods of the invention. These disorders include impulse controldisorders, panic syndrome, general anxiety disorder, phobic syndromes ofall types, mania, manic depressive illness, hypomania, unipolardepression, stress disorders, PTSD, somatoform disorders, personalitydisorders, psychosis, and schizophrenia.

“Impulse Control Disorders” are characterized by harmful behaviorsperformed in response to irresistible impulses. The essential feature ofan impulse control disorder is the failure to resist an impulse, drive,or temptation to perform an act that is harmful to the person or toothers. Symptoms include an increasing sense of tension or arousalbefore committing an act, and then experiences pleasure, gratification,or release at the time of committing the act. After the act isperformed, there may or may not be regret or guilt. Numerous disorderscan be characterized as impulse control disorders including intermittentexplosive disorder, kleptomania, pathological gambling, pyromania,trichotillomania, compulsive buying or shopping, repetitiveself-mutilation, nonparaphilic sexual addictions, severe nail biting,compulsive skin picking, personality disorders with impulsive features,attention deficit/hyperactivity disorder, eating disorders characterizedby binge eating, and substance abuse disorders such as alcoholism anddrug addiction. Binge eating disorder and bulimia are also sometimesclassified as impulse control disorders.

Packaged Pharmaceutical Preparations

Also provided are packaged pharmaceutical preparations for practicingthe subject methods. The packaged preparation contains a composition ofthe invention in a sealed container, and typically contains a pluralityof individual dosage forms each in a sealed housing, as in a blisterpack, but could also contain one or more dosage forms in a single sealedcontainer. Optionally, dosage forms with lower doses of one or bothactive agents can also be included, for dose titration and doseescalation.

In certain embodiments, the packaged pharmaceutical preparations includeinstructions for a patient to carry out drug administration to achieveweight loss, treat obesity, treat conditions associated with obesity, ortreat other conditions as explained earlier herein. For instance, theinstructions may include the daily dose of topiramate to be taken, thedaily dose of phentermine or other sympathomimetic agent to be taken,and/or the dosing regimen for self-administration of a controlledrelease dosage form containing topiramate and optionally the secondactive agent. The instructions may be recorded on a suitable recordingmedium or printed on a substrate such as paper or plastic. As such, theinstructions may be present as a package insert, in the labeling of thepackage, container(s), or components thereof (i.e., associated with thepackaging or sub-packaging), etc. In other embodiments, the instructionsare present as an electronic storage data file present on a suitablecomputer readable storage medium, e.g. CD-ROM, diskette, etc. In yetother embodiments, the actual instructions are not present, but meansfor obtaining the instructions from a remote source, e.g. via theinterne, are provided. As an example, a web address might be included todirect patients to a website where the instructions can be viewed and/orfrom which the instructions can be downloaded. As with the instructionsper se, this means for obtaining the instructions is recorded on asuitable substrate.

Some or all of the included components may be packaged in suitablepackaging to maintain sterility. In many embodiments, the components arepackaged in a containment element to provide a single, easily handledunit, where the containment element, e.g., box or analogous structure,may or may not be an airtight container, e.g., to further preserve thesterility of some or all of the components. In certain aspects, a sealedpackage of controlled release dosage forms is provided wherein thedosage forms contain phentermine in immediate release form andtopiramate in controlled release, e.g., sustained release and delayedrelease form. Alternatively, separate phentermine-containing andtopiramate-containing dosage forms may be included.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the present invention, and are not intended to limit thescope of what the inventors regard as their invention nor are theyintended to represent that the experiments below are all or the onlyexperiments performed. Efforts have been made to ensure accuracy withrespect to numbers used (e.g. amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Celsius, andpressure is at or near atmospheric.

Example 1

Controlled release topiramate beads are made using an extrusionspheronization process to produce a matrix core comprised of topiramate,40.0% w/w; microcrystalline cellulose (Avicel® PH102), 56.5% w/w; andMethocel™ A15 LV, 3.5% w/w. The topiramate cores were then coated withethyl cellulose, 5.47% w/w, and Povidone K30, 2.39% w/w.

The composition of the topiramate beads so prepared is as follows:

Component % w/w topiramate 36.85 microcrystalline cellulose, 52.05(Avicel ® PH102) Methylcellulose  3.22 (Methocel ™ A15 LV)ethylcellulose  5.47 Polyvinylpyrrolidone  2.39 (Povidone K30)

Phentermine hydrochloride was coated onto sugar spheres to provideimmediate release phentermine beads. Both sets of beads were thenencapsulated into each of a plurality of capsules.

Example 2

In a study comparing controlled-release formulation of topiramateaccording to the present invention versus immediate release topiramate(Topamax®) in combination with phentermine, the controlled releaseformulation of the instant invention of topiramate had a 10-15% lowereffect on phentermine exposure (FIG. 2).

The mean and statistical comparisons for plasma phentermine PKparameters at steady state in multiple dose administrations aresummarized in Table 2.

TABLE 2 Arithmetic Mean (SD) and Statistical Comparison ofPharmacokinetic Parameters for Plasma Phentermine Treatment 2 VersusTreatment 4 Mean +/− SD 90% % Pharmacokinetic Treatment 2 Treatment 4Confidence Mean Parameters (N = 13) (N = 12) Intervals Ratio AUC_(0-tau)2250 +/− 563  2530 +/− 644  (75.6, 105.3) 89.2 (ng * hr/mL) AUC₀₋₉₆ 4640+/− 1570 5550 +/− 1960 (67.1, 105.0) 84.0 (ng * hr/mL) AUC_(0-t) 4640+/− 1570 5550 +/− 1960 (67.1, 105.0) 84.0 (ng * hr/mL) C_(max,ss)  114+/− 23.6  127 +/− 27.6 (78.8, 104.5) 90.7 (ng * hr/mL) C_(min,ss) 9.84+/− 7.24 14.6 +/− 11.3 (42.5, 109.0) 68.1 (ng * hr/mL) t_(max) (hr) 4.014.54 (1.04, 7.00) (1.00, 10.0) T_(1/2) (hr) 23.3 +/− 6.17 26.3 +/− 7.43CL_(ss)/F (L/hr) 7.10 +/− 1.89 6.38 +/− 2.00 V₂/F (L/hr)  229 +/− 45.3 232 +/− 58.5 t_(max) is presented as median (minimum, maximum)Parameters were dose-normalized and In-transformed prior to analysis. %Mean Ratio = 100 * ex[(Treatment 2 − Treatment 4) for In-transformedparameters Treatment 1 (Test): 7.5 mg phentermine/50 mg topiramate(Formulation A) Treatment 2 (Test): 15 mg phentermine/100 mg topiramate(Formulation A) Treatment 4 (Reference): 15 mg phentermine/100 mgtopiramate Source: Tables 14.2.1.8, 14.2.1.10, 14.2.1.12, and 14.2.1.17

These data indicate a lower maximum and extent of phentermine exposurebetween tests versus reference treatments after multiple-doseadministration. As such, the controlled release formulation oftopiramate reduced drug interaction with phentermine which in turn willreduce further side effects associated with phentermine.

1. A controlled release composition for treating obesity, diabetes,sleep apnea, or a related condition in a subject comprising: aneffective amount of topiramate and phentermine.
 2. A method foreffecting weight loss in a subject, comprising administering to thesubject continually over a significant period of time a daily dose ofphentermine in combination therewith a daily dose of topiramate selectedto prevent the loss of effectiveness of phentermine alone.